This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Uterine Natural Killer cells (uNK) are a unique subpopulation of CD56brightCD16- lymphocytes that increase in number after ovulation, and reach their peak numbers during the first trimester of pregnancy. Although lymphocytes are generally thought to play a role in host defense, there is increasing evidence that the primary function of uNK cells is not immunological but rather they may play a role in angiogenesis, trophoblast invasion and spiral artery remodeling. Women who experience recurrent miscarriages and failure of implantation have been reported to be deficient in uNK cells. Thus proper localization and function of uNK cells is necessary for normal fetal development. The origins of uNK cells are unclear. During pregnancy, their number expands greatly, either through increased recruitment to the uterus, or via expansion of resident populations. Approximately 10% of peripheral NK cells (pNK) are of the uNK phenotype (CD56brightCD16-), and have been proposed to be selectively recruited to the uterus during pregnancy. However, recently it has been reported that TGF? supports conversion of CD56dimCD16+ cells towards a CD56brightCD16- phenotype, and that decidual stromal cells produce TGF?. Based on these findings, we hypothesize that CD56dimCD16+ pNK cells are recruited to the uterus, where they are then induced towards the CD56brightCD16- uNK phenotype by TGF?. If this model is correct, then CD56dimCD16+ cells would be predicted to be preferentially recruited to uterine endothelium as compared to CD56brightCD16- cells. We will test this hypothesis in the following aims:
Specific Aim 1. Determine the relative adhesive ability of specific human NK cell subpopulations to frozen sections of mouse placenta.
Specific Aim 2. Utilizing cultured human uterine micrrovascular endothelial cells (HUtMVEC), examine the entire rolling-arrest-transmigration cascade of uNK recruitment and test the transmigration capability of each subpopulation. Specifically, we will (a) test the effect of estrogen, progesterone, and LH on expression of adhesion molecules by HUtMVEC in culture, to identify conditions where they are upregulated;(b) using the conditions defined from part a, establish a cell-cell adhesion assay for human NK cells with HUtMVEC;and (c) develop an in vitro flow assay using HUtMVEC induced to express adhesion receptors, and defined human NK subpopulations to recapitulate rolling, arrest and transendothelial migration in vitro. These studies will lead to a better understanding of the origin of human uNK cells, their homing mechanism, and their role in maintenance of normal pregnancy.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-6 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Women and Infants Hospital-Rhode Island
United States
Zip Code
Chen, X; Rivard, L; Naqvi, S et al. (2016) Expression and localization of Inter-alpha Inhibitors in rodent brain. Neuroscience 324:69-81
Uzun, Alper; Sahin, Yavuz; Schuster, Jessica S et al. (2016) Structural and genomic variation in preterm birth. Pediatr Res 80:829-836
Conicella, Alexander E; Zerze, Gül H; Mittal, Jeetain et al. (2016) ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure 24:1537-49
Brodsky, Alexander S; Xiong, Jinjun; Yang, Dongfang et al. (2016) Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer. BMC Cancer 16:274
Uzun, Alper; Triche, Elizabeth W; Schuster, Jessica et al. (2016) dbPEC: a comprehensive literature-based database for preeclampsia related genes and phenotypes. Database (Oxford) 2016:
Chow, Brian D W; Reardon, Juliann L; Perry, Emily O et al. (2016) Host Defense Proteins in Breast Milk and Neonatal Yeast Colonization. J Hum Lact 32:168-73
Uzun, Alper; Schuster, Jessica; McGonnigal, Bethany et al. (2016) Targeted Sequencing and Meta-Analysis of Preterm Birth. PLoS One 11:e0155021
Cheng, Shi-Bin; Nakashima, Akitoshi; Sharma, Surendra (2016) Understanding Pre-Eclampsia Using Alzheimer's Etiology: An Intriguing Viewpoint. Am J Reprod Immunol 75:372-81
Glass, Kyle A; Longley, Sarah J; Bliss, Joseph M et al. (2015) Protection of Candida parapsilosis from neutrophil killing through internalization by human endothelial cells. Virulence 6:504-14
Zhang, Jiyong; Sadowska, Grazyna B; Chen, Xiaodi et al. (2015) Anti-IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus. FASEB J 29:1739-53

Showing the most recent 10 out of 153 publications